Prostate cancer is a common but complex disease with a number of unresolved issues surrounding its natural history. These include concerns with screening, detection, and treatment, and reflect the substantial heterogeneity in prostate tumors: some will remain latent and have little impact on morbidity, whereas others progress rapidly in a potentially lethal manner. Genetic factors likely underlie some of these differences, and we propose a comprehensive evaluation of the genetic basis of prostate cancer risk and progression in a large, well-characterized study population. In particular, we will investigate rar functional variants across the exome and common SNPs across the genome. Our sample encompasses 8,078 prostate cancer cases and 8,078 age and ethnicity matched controls nested within the Kaiser / USCF Research Program on Genes, Environment and Health cohort. This population has existing genome-wide SNP measures, and uniformly collected clinical information on prostate cancer screening, diagnoses, and progression. We plan to type the new exome array on the cases and controls to assess the functional variants in protein coding regions across the human genome. With these data we will address our hypothesis that these genetic factors can be used to predict-and underlie an increasing proportion of the variation in-prostate cancer risk and progression. This project provides an efficient and innovative opportunity to obtain a comprehensive understanding of how these factors impact the natural history of prostate cancer. Our findings should supply important insights into the underlying mechanism of disease, with the ultimate goal of helping to improve screening and treatment for prostate cancer.